This invention relates to a process for making an o-aryl benzonitrile by reacting o-chlorobenzonitrile (OCBN) with a substituted phenylzinc halide. In particular, it relates to a method of making o-tolylbenzonitrile (OTBN) by reacting OCBN with p-tolylzinc chloride in the presence of a nickel catalyst, an ethereal solvent, and N-methylpyrrolidinone (NMP) as a cosolvent.
OTBN can be used as a building block in a new class of pharmaceutically active materials--the angiotensin-II-antagonists. A number of coupling approaches have been developed for making OTBN. For example, it can be made via direct coupling of aryl iodides under classical Ullman conditions. OTBN can also be made by reacting Grignard reagent with o-bromobenzonitrile (OBBN) or OCBN in the presence of a transition metal catalyst (Pd, Ni, or Mn). However, the high cost of raw materials, such as aryl iodide and OBBN, has limited the wide application of these methods.
The reaction of OBBN or OCBN with p-tolylboronic acid (Suzuki reaction) also gives a good yield of OTBN. This reaction performs well with an aryl bromide as an electrophile, but an expensive water soluble or bidentate ligand is required for the reaction of an aryl chloride. The reaction of OBBN with organozinc reagent (Neggish reaction) to make OTBN has also been tried.